WO1996011714A1

WO1996011714A1 - Composite bone cement

Info

Publication number: WO1996011714A1
Application number: PCT/FR1995/001364
Authority: WO
Inventors: Jacques Dejou; Wilhelm Joseph Pertot; Philippe Rolland; Jean-Pierre Proust; Marcel Camps
Original assignee: Euros
Priority date: 1994-10-17
Filing date: 1995-10-17
Publication date: 1996-04-25
Also published as: EP0797458A1; FR2725625A1; FR2725625B1

Abstract

The present invention relates to a composite bone cement characterized in that it is comprised of a biocompatible powdery mineral filler (a) providing for the mechanical solidity of the cement; a biocompatible powdery organic filler (b) comprising the mixture of porous polymer particles providing for the penetration of fluids in the cement (b1) and biodegradable polymer particles designed to leave large diameter pores in the cement obtained in order to create osteoconductivity (b2); and a binding agent (c) consisting of an organic matrix Bis GMA and its activator.

Description

The present invention relates to a new bone cement, useful as a composite filling material, hardenable by polymerization and gradually colonizable by bone. The bone cements known in the prior art, generally comprise a polymer powder and a crosslinking agent intended to ensure the hardening of the cement, (EP-A-0 430 705, EP-A-0 361 408), optionally added of a mineral filler (EP-A-0 225 706, WO-A- 82/01990). These bone cements are generally prepared by mixing on the one hand a powder comprising the polymer and optionally the mineral filler, and on the other hand a liquid comprising monomers and polymerization initiators so as to react with the polymer powder, forming a resin which hardens on drying. Such cements are described in particular in application FR-A-

2,670 1,14, with, depending on the monomers used, the possibility of obtaining water-soluble elements and non-water-soluble elements, formed in situ by polymerization, interconnected but not present in the form of particles.

In the production of a bone cement, it is also important to consider the evolution of the latter, with the progressive resorption of the polymer resin and its replacement by the bone tissue.

It is therefore important to provide a polymer resin which promotes the setting of bone tissue and whose resorption does not reduce the mechanical properties of bone cement. The present invention therefore relates to a new bone cement consisting of:

- a biocompatible powdery mineral filler (a) ensuring the mechanical strength of the cement;

a biocompatible organic pulverulent filler (b) comprising the mixture, on the one hand of porous polymer particles ensuring the penetration of fluids in the cement (bl), and on the other hand of biodegradable polymer particles intended to leave pores of large diameter in the cement obtained to have osteoconduction (b2); and

- a binding agent (c). In general, the binding agent is used in the form of a liquid, mixed extemporaneously with a powder (pre-polymerized resinous powder particle) to form a paste. The current The invention therefore also relates to a pulverulent mixture consisting of the mineral filler (a) and the organic filler (b) defined above, useful for preparing the cement according to the invention, by subsequently mixing it with an appropriate binding agent, in the form preformed powder or paste. The biocompatible powdery mineral filler (a) consists of a material ensuring the mechanical strength of the cement and having good biocompatibility with regard to the medium in which the cement will be integrated.

It must be chemically compatible with the other constituents of the latter so as not to cause disaggregation phenomena. Furthermore, it must not cause irritation and other infections of the environment in which it is integrated.

The pulverulent mineral filler (a) generally consists of a silicate material, natural or synthetic, in particular by powder of glass, ceramic, baked clay, as well as by powder of aluminosilicates, such as for example kaolin or with a phosphocalcic compound.

The particles of mineral filler are substantially spherical and have an average diameter of less than 50 μm, advantageously between 5 and 20 μm, even more advantageously of approximately 10 μm.

By mean diameter is meant according to the invention the dimensions of the meshes of a sieve in which the particles flow by gravity.

To promote its chemical compatibility with the other constituents of the cement according to the invention, the particles of mineral filler will advantageously be silane, that is to say coated with a compatibilizing silane, for example methacryloxypropyl-trimethoxy-silane.

The biocompatible organic pulverulent filler (b) consists of a mixture of two types of polymer particles, on the one hand porous polymer particles (b1) and on the other hand of biodegradable polymer particles (b2).

The porous particles (bl) are intended to promote the penetration of fluids into the cement in order to promote the development of bone tissue, so that it gradually replaces the cement.

The particles (b1) are essentially in the form of porous balls or spheres, the average diameter of which is greater than or equal to 500 μm and the average porosity is between 30 and 70% (measured with a mercury porosimeter). They consist of a biocompatible polymeric material, that is to say having harmless properties with respect to the medium in which the cement will be used, also chemically compatible with the other constituents of the cement. The polymeric material will also be biodegradable, that is to say absorbable by the organism in which the cement is used, the rate of resorption being however slow enough to allow the maintenance of the cement and of its cohesion during the development of the bone tissue. by penetration of physiological fluids through the pores.

These are in particular conventional biocompatible biopolymers, in particular crosslinked copolymers of glycol (meth) acrylate and of divinylbenzene.

These copolymers are advantageously obtained by emulsion copolymerization, a two-phase aqueous suspension consisting on the one hand of a mixture of glycol (meth) acrylate, of divinylbenzene and of toluene in respective weight proportions of between 8/1 / 10 and 4 / 1/6, preferably 6/1/8.

The initiation of the copolymerization is carried out by a radical polymerization initiator soluble in the above organic phase but insoluble in water. The initiator is used in proportions of between 0J and 1% by weight.

The second phase, the aqueous biphasic phase also contains gum arabic, in particular acacia gum arabic (titrating from 0.5 to 1.5%) and a surfactant such as metal lauryl sulfate alkaline, especially sodium. In this aqueous phase, the organic phase is divided into droplets which solidify by polymerization giving the macroporous beads.

The biodegradable polymer particles (b2) are made up of a rapidly biodegradable polymeric material to give way to pores in the cement, unlike the material constituting the porous particles (b1) whose resorption must be slow and controlled.

They are also essentially in the form of balls, or spheres, the average diameter of which is between 150 and 400 μm, so as to leave in the cement pores of the same diameter creating osteoconduction.

The particles (b2) consist of usual biodegradable hydrophilic (co) polymers, in particular (co) polymers comprising units derived from (meth) acrylic acid and / or lactic acid and / or glycolic acid, or polyacryloid acid.

Advantageously, these are (co) polymers of the acid obtained by mass polymerization of the monomers of general formula CH2 = CH-CORl for which RI represents a halogen, in particular chlorine or bromine, a sugar , or a radical of formula

-O-CH (R2) -CH ₂ (R3) in which R2 represents a hydroxy carbonyl group, a lower C 1 -C ₄ alkoxy carbonyl group, for example ethoxy carbonyl, or a hydroxy group,

R3 represents a hydrogen atom or a hydroxy group, or alternatively

R2 and R3 together form a bond -O-CH ₂ -O-. According to another embodiment of the invention, the biodegradable polymer is a copolymer of lactic acid and glycolic acid comprising monomers L and D of lactic acid, in particular copolymers obtained by the polymerization of L-lactide , glycolid ci of D-lactide in a weight ratio close to 3: 4: 3, respectively. Finally, the binding agent (c) consists of a resin p <>l> πκτe. formed extemporaneously by mixing monomers and / or p. MIR Γ of low molecular weight and a polymerization initiator.

This polymer resin must, of course, be chemically combined with the other constituents of the cement according to Riin Cmiυn. lk- must also have the characteristics of biocompatibility common to all of these constituents, taking into account their medical use.

Generally, the polymer resin of the binding agent (c) is a bis-GMA resin.

Advantageously, the polymer resin is obtained by polymerization of ethylene glycol dimethacrylate.

The cement according to the invention is prepared by mixing and kneading the pulverulent mixture (a and b) according to the invention with a solution or a paste comprising the binding agent (c), in suitable proportions.

According to another embodiment of the invention, the cement is obtained by mixing the pulverulent mixture with a powder consisting of monomers and / or polymers of low molecular weight, precursors of the polymer resin, then adding to the mixture obtained an aqueous solution comprising a polymerization initiator, such as benzoyl peroxide, and if necessary an agent delaying the polymerization.

Advantageously, the powdery mineral filler (a) represents between 60 and 80% by weight of the powdery mixture (a and b), preferably about 70% by weight.

Furthermore, the weight ratio (b1) / (b2) between the two constituents of the pulverulent organic charge (b) is advantageously between 0.20 and 0.35. Finally, the weight ratio between the constituents of the pulverulent mixture (a and b) and the binding agent (c) is advantageously between 4 and 5.5.

Other characteristics of the invention will appear on reading the examples below. EXAMPLE 1 Preparation of porous beads (bl)

Their manufacture was developed with the collaboration of Professor CAMPS in Marseille, laboratory of artificial polymers, Faculty of Sciences St-CHARLES.

The quantities given below were determined after four tests, which made it possible to adapt the diameter of the spheres obtained as well as their degree of porosity and their mechanical strength, a) Preparation of the aqueous phase (solution Λ)

In a 2-liter beaker, mix:

- 167 cc of gum arabic solution (made from 3.4 g of acacia gum)

- 170 cc of deionized water, until homogenization and the aqueous phase is raised to a temperature of 65 ° to 75 °. Gum arabic is used to coat the droplets of polymer obtained; it is a protective colloid. b) Preparation of the organic phase (solution B)

In an Erlen, the following constituents are mixed:

- crosslinking agent: 5 g of divinylbenzene

- organic matrix: 30 g of ethylene glycol dimethacrylate (C A)

- blowing agent: 40 ml of toluene - initiator of the radical reaction: 0.45 g of benzoyl peroxide at

18% water. The GMA + divinylbenzene + toluene mixture with the reaction initiator (benzoyl peroxide) is carried out at the last moment, to avoid immediate polymerization. c) Mixing of the two phases The various constituents of phase B are incorporated into the phase

At temperature when the benzoyl peroxide is dissolved.

The rotation speed of the paddle agitator is increased in order to mix the mixture well (10 min). d) Emulsion (solution C) - 10 cc of lauryl sulfate solution at 45 mg per 10 ce when the quantity of surfactants increases, the diameter of the spheres decreases. With this quantity of lauryl sulfate, the speed of rotation of the paddle stirrer must be 800 revolutions / minute for the desired diameter. Duration 5 hours. e) Precipitation and refining of macrophiles

The mixture of phases A + B and the emulsion C are added to 200 ml of deionized water.

Stirred for 12 hours at 400 revolutions / minute, without heating, to refine the shape of the beads. 0 Fi ltering

The lauryl sulfate and gum arabic are removed by washing with ordinary water.

The organic phase is removed by washing with methanol. g) Evaporation of toluene The pore-forming agent is eliminated in a Soxhlet. h) Vacuum drying at 100 °

The porous beads thus obtained are dried under vacuum at 100 ° C. EXAMPLE 2 Preparation of the biodccomposable beads (b2)

Preparation of microbeads of 150 μ to 400 μ in diameter, in order to create pores of the same diameter in the cement.

The polymer which has been chosen is a copolymer of lactic acid and glycolic acid (PLa 30 Ga 40).

It comprises 30% L lactide, 40% glycolide and 30% D lactide, but is called PLa 30 Ga 40 because the nomenclature requires that only the amounts of L lactide and glycolide be mentioned. a) Preparation of the aqueous phase

In a 2-liter beaker, mix: - 8 g of polyvinyl alcohol

- 1 liter of distilled water

- 10 g of sodium chloride which is stirred for 2 hours to obtain a clear and homogeneous phase. b) Preparation of the organic phase

In a 50 ml stoppered Erlenmeyer, we mix:

- 4 g of copolymer,

- 25 ml of dichloromethane which is stirred until homogeneous, about 10 minutes. The bubbles present in the phase are removed by passing over a vibrator. c) Mixing of the two phases

The phases obtained above are mixed and stirred with a paddle stirrer for 4 hours at 600 rpm in a hood. d) Filtration

The solution obtained is rinsed and filtered in a fry on a vacuum flask after 10 minutes of decanting. The micropheres of biopolymer (b2) are recovered. e) Rinsing with distilled water Then rinse to remove the last traces of soh ant. f) Drying in a dryer

Leave to dry for a minimum of 15 days at a temperature of 40 ° C. g) Sieving The beads obtained are then placed on a 400 μ sieve.

EXAMPLE 3 Preparation of a powder mixture

The powder mixture consists of the following materials, per 100 g of powder:

- 48.4 g of silane mineral fillers, based on quartz, barium glass and silica, with a particle size of approximately 10 μm;

- 10.9 g of porous beads (bl) obtained according to the protocol described in Example 1;

- 39.9 g of biodegradable polymer beads (b2) obtained according to the protocol described in Example 2. The constituents are mixed by kneading.

EXAMPLE 4 Preparation of a bone cement 100 g of the pulverulent mixture obtained above are added to 21.06 g of a pulverulent bis-GMA resinous organic matrix.

To the pulverulent mixture obtained, an aqueous solution is added comprising a polymerization initiator, in particular benzoyl peroxide and an appropriate retarding agent so as to regulate the setting time of the cement according to the invention. The cement obtained may further comprise an appropriate dye.

The physico-mechanical properties of the final product will be at least equal to those given by the ISO 5833 standard relating to bone cements based on PMMA.

Claims

1. Composite bone cement, characterized in that it consists of: - a biocompatible powdery mineral filler (a) ensuring the mechanical strength of the cement;

a biocompatible organic pulverulent filler (b) comprising the mixture on the one hand of porous polymer particles ensuring the penetration of fluids in the cement and on the other hand of bio-decomposable polymer particles intended to leave large pores in the cement obtained ensuring osteoconductivity (b2); and

- a binding agent (c).

2. Cement according to claim 1, characterized in that the pulverulent mineral filler (a) consists of particles of a silicate material, natural or synthetic, in particular by powder of glass, ceramic, baked clay , as well as with aluminosilicate powder, such as for example kaolin or a phosphocalcic compound.

3. Cement according to one of claims 1 or 2, characterized in that the particles of mineral filler are substantially spherical and have an average diameter of less than 50 μm, advantageously between 5 and 20 μm, even more advantageously of approximately 10 μm .

4. Cement according to one of claims 1 to 3, characterized in that the particles are coated with a compatibilizing silane, for example methacryloxypropyl-trimethoxy-silane.

5. Cement according to one of claims 1 to 4, characterized in that the porous polymer particles (bl) are essentially in the form of porous balls or spheres, the average diameter of which is greater than or equal to 500 μm and the average porosity is between 30 and 70% by volume.

6. Cement according to one of claims 1 to 5, characterized in that the porous polymer particles (b1) consist of a resin of crosslinked copolymer of glycol (meth) acrylate and of divinylbenzene.

7. Cement according to one of claims 1 to 6, characterized in that the bio-decomposable polymer particles (b2) are in the form of balls, or spheres, whose average diameter is between 150 and 400 microns.

8. Cement according to one of claims 1 to 7, characterized in that the biodegradable polymer particles (b2) consist of usual (co) hydrophilic biodecomposable polymers, in particular (Co) polymers comprising units derived from (meth) acrylic acid and / or lactic acid and / or glycolic acid and / or polyacryloid acid.

9. Cement according to claim 8, characterized in that the particles (b2) consist of (co) polymers obtained by mass polymerization of the monomers of formula:

-CH ₂ = CH-CORl for which RI represents a hydrophilic group chosen from a halogen, in particular a chlorine or a bromine, a sugar, or a radical of formula

-O-CH (R2) -CH ₂ (R3) in which R2 represents a hydroxy carbonyl group, a lower C ₁ -C ₄ alkoxy carbonyl group, for example ethoxy carbonyl, or a hydroxy group, R3 represents an atom of hydrogen or a hydroxy group, or

R2 and R3 together form an -O-CFb-O- bond.

10. Cement according to claim 8, characterized in that the particles (b2) consist of a copolymer of lactic acid and glycolic acid comprising monomers L and D of lactic acid, in particular copolymers obtained by the polymerization of L-lactide, glycolide and D-lactide in a weight ratio close to 3: 4: 3, respectively.

1 1. Cement according to one of claims 1 to 10, characterized in that the binding agent (c) consists of a polymer resin, formed extemporaneously by mixing monomers and / or polymers of low molecular weight and an initiator polymerization.

12. Cement according to claim 1 1, characterized in that the polymer resin of the binding agent (c) is a bis-GMA resin.

13. Cement according to one of claims 1 to 12, characterized in that the powdery mineral filler (a) represents between 60 and 80% by weight of the powdery mixture (a and b), preferably about 70% by weight.

14. Cement according to one of claims 1 to 13, characterized in that the weight ratio (bl) / (b2) between the two constituents of the pulverulent organic filler (b) is advantageously between 0.20 and 0.35 .

15. Cement according to one of claims 1 to 14, characterized in that the weight ratio between the constituents of the powder mixture (a and b) and the binding agent (c) is advantageously between 4 and 5.5.

16. Pulverulent mixture, useful in particular for the preparation of a bone cement, characterized in that it comprises a biocompatible mineral filler (a) and a biocompatible organic filler (b), as defined in claims 1 to 15.